SK277925B6 - Method of stereoselective preparation of phenylisoserine derivatives - Google Patents

Abstract

Compounds with general formula I, where R means the phenyl radical or tert.butoxy-radical and R exp.1 means protective group of hydroxylic group, are prepare so, that benzylamine is influenced by agent which enables to leade the bemzoyl or tert. butoxy carbonyle group, the intermediate of these reaction is after double anioisation influenced by acrolein by beginning of alcohol in form of configuration "E" and "Z" mixture, at which is configuration "E" separed from this mixture consequently is realized the protection of hydroxylic group and so protected alcohol is oxided by begining of derivative with general formula I in configuration "E" whose enantiomers are casually separated.

Description

Technical field

The present invention relates to a process for the stereoselective preparation of the phenylioserine derivatives of the general formula I:

NH-CO-R

wherein R is a phenyl radical or t-butoxy radical and R * is a hydroxyl protecting group.

In the general formula, IR ¹ is in particular a methoxy radical, a 1-ethoxyethyl radical, a benzyloxymethyl radical, a (beta-trimethylsilylethoxy) methyl radical, a tetrahydropyranyl radical or a 2,2,2-trichloroethoxycarbonyl radical. Preferably R ¹ represents a 1-ethoxyethyl radical.

The products of the formula I are used for the preparation of baccatin m and 10-deacetylbaccatin H1 derivatives of the formula Π:

The racemic product of formula (I) may be reacted and then the diastereoisomers of the product of formula (H) may be separated, or each of the enantiomers of the product of formula (I) separately reacted and reacted with the product of formula (O).

SUMMARY OF THE INVENTION

The acid of formula I (configuration Έ, racemic mixture) according to the invention can be obtained from benzylamine.

The benzylamine is converted to the product of formula IV by the action of a benzoyl or tert-butoxycarbonyl group introducing agent:

NH-CO-R αν] in which R is as defined above, and this product is reacted with acrolein after a double anion to form an alcohol of formula V:

r

NH-CO-R

wherein R represents a phenyl radical or tert-butoxy radical and R ³ represents a hydrogen atom or an acetyl radical.

The products of formula Π in which R represents a phenyl radical correspond to taxol and 10-deacetyltaxol and the products of formula Π in which R represents a tert-butoxy radical correspond to those described in European patent EP 253 738.

The products of formula H and in particular the product of formula Π, wherein R ³ is H, having the configuration 2'R, 3S, have particularly advantageous antitumour and antileukemic properties.

BACKGROUND OF THE INVENTION

The products of formula Π can be obtained by treating a taxane derivative of formula ΠΙ with a product of formula I:

Wherein R ⁵ is an acetyl radical or a hydroxyl protecting group and R ⁴ is a hydroxyl protecting group, followed by replacement of the protecting groups R ¹ and R ⁴ and optionally R ⁵ with a hydrogen atom under the conditions described in JN. Denis et al. in J. Amer. Chem. Soc., 770 (17) 5917-5919 (1988).

in which R is as defined above, in the form of a mixture of configurations E and Z, comprising in particular the configuration E:

NH-CO-R

C 6 H 8 OH

The alcohol of the formula Va, which is separated from the mixture of configurations E and Z, is oxidized to the acid of the formula after protection of the hydroxyl group

I.

The product of formula (IV) is generally obtainable by treatment with a benzoyl or tert-butoxycarbonyl group, which is preferably benzoyl chloride or di-tert-butyldicarbonate. Generally, the reaction is carried out in an organic solvent such as methylene chloride in the presence of a mineral base such as sodium hydroxide or sodium bicarbonate or carbonate, or an organic base such as triethylamine or 4-dimethylaminopyridine at 0 to 50 ° C.

The double anionization of the product of formula (IV) is generally carried out using two equivalents of an organolithium derivative such as sec-butyllithium, operating in an anhydrous organic solvent such as tetrahydrofuran at a temperature below -50 ° C, preferably near -78 ° C.

In general, the reaction of acrolein with a dianion of the product of formula IV is carried out by adding acrolein, preferably freshly distilled, to a solution of said dianion of the product of formula IV, which has previously been cooled to a temperature near -100 ° C. After hydrolysis, the product of formula V is obtained in the form of a mixture of diastereoisomers Έ and Z and from this mixture the E configuration of the product of formula Va is separated by chromatography.

The protection of the hydroxyl group of the alcohol of formula (Va) is carried out under conditions used in the preparation of ethers and acetals, for example by the procedures described in J-N. Denis et al. in J. Org. Chem., 51, 46-50 (1986).

The oxidation of the hydroxyl-protected alcohol of the formula (Va) is preferably carried out with an alkali metal periodate (sodium periodate) in the presence of a catalytic amount of ruthenium salt (ruthenium chloride) and sodium bicarbonate, operating in an aqueous-organic environment such as tetracturomethane, acetonitrile. and water. Generally, this reaction is carried out at a temperature near 20 ° C.

Said oxidation may also be carried out with potassium permanganate, for example in the presence of adogen in a mixture of pentane and water or in the presence of an alquate or 18-dicyclohexyl-6-crown in dichloromethane or a mixture of pyridine and water. Triethylbenzylammonium permanganate can also be used in the presence of pyridine in dichloromethane.

The product of formula 1 (configuration E, racemic mixture) can be resolved into its enantiomers and in particular to the enantiomer 2R, 3S, for example by the procedure described by D. Petterson in These de l'Université de Lund (Sweden), p. 27-28 (1989).

In the following, the process according to the invention will be explained in more detail by means of specific examples thereof, which, however, are only illustrative and do not limit the actual scope of the invention as defined by the claims.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

In a 50 cm ³ single neck flask with condenser and magnetic stirrer, under argon atmosphere, 218.5 µl (214.3 mg, 2 millimoles) of benzylamine and 10 cm ^{3 of} anhydrous dichloromethane are introduced. To this solution was added 418 µl (303 mg, 3 millimoles) of triethylamine and 524 mg (2.4 millimoles) of pure di-tert-butyl dicarbonate in small portions (exothermic reaction). When the addition is complete, the mixture is allowed to react for 4 hours at a temperature in the region of 20 ° C, then the reaction mixture is diluted with 40 cm ^{3 of} dichloromethane. The organic phase is washed four times with 5 cm ^{3 of} water and once with 5 cm ^{3 of} saturated aqueous sodium chloride solution. The organic phase is then dried over anhydrous sodium sulfate. After filtration, the dichloromethane is removed under reduced pressure in a rotary evaporator.

The residue (505 mg) is purified by chromatography on a silica gel column, eluting with a mixture of ethyl acetate and methylene chloride (5:95 by volume). 406 mg (1.96 mmol) of tert-butylbenzylcarbamate are obtained in the form of a white solid in a yield of 98%. This product has the following characteristics:

- melting point: 55.5 - 56.5 ° C (hexane);

- infrared spectrum (film):

characteristic absorption bands at:

3350.3315, 3080, 3060, 3040, 3010.2980.2960, 2930.1680, 1550, 1450, 1442.1395.1370, 1315, 1290.1255.1180, 1140, 1080.1055.1035, 950, 930.918, 865,770, 750, 725 and 700 cm ^-1 ;

@ 1 H NMR (CDCl3): 300 MHz; CDCl 1; chemical shifts in ppm; coupling constant J in Hz / 1.46 / s, 9HA

4.3 / d J = 5.7; H /; 4.84 / sec. Width, IHA ₁₃ 7.22-7.34 Λη, 5HA

- C-nuclear magnetic resonance spectrum:

(CDCl ₃ / 28.38) CH ₃ A 44.69 / CH ₂ A

79.43 (CA 127.27 / CHA, 127.41 / CHA, 128.54 / CHA 138.93 (CA 155.84 / C).

Example 2

4.2 g (20.3 millimoles) of tert-butylbenzylcarbamate, 40 cm ^{3 of} anhydrous tetrahydrofuran and 6.5 cm ³ (5 cm ³ ) are successively introduced into a 250 cm ³ single-necked flask equipped with a magnetic stirrer. 0 g, 43 millimoles) of tetramethylethylenediamine. The solution obtained is cooled to -78 ° C and then 60 cm ³ (60 millimoles) of a 1M solution of sec-butyllithium in hexane are added dropwise. The mixture was allowed to react at this temperature for 3 hours, then cooled to -100 ° C. Freshly distilled acrolein (3 cm ³⁾ (2.5 g, 44.9 millimoles) was added and the mixture was allowed to react at the same temperature for 3 and 4 minutes and then for one hour at -78 ° C. The reaction mixture obtained is then hydrolysed at -78 DEG C. with 20 cm @ ^{3 of} water and then extracted twice with 30 cm @ ^{3 of} ether. The organic phases are combined and then washed twice with 20 cm ^{3 of} water and once with 10 cm ^{3 of} saturated aqueous sodium chloride solution. The combined organic phases are then dried over anhydrous sodium sulfate. After filtration, the solvents were stripped off under reduced pressure. The residue (11.6 g) was purified on a silica gel column using a 95: 5 mixture of methylene chloride and ether as the eluent.

In a yield of 49%, 2.606 g (9.91 mmol) of 1-phenyl-1-tert-butoxycarbonylamino-2-hydroxy-3-butene are obtained as a 6: 1 mixture of diastereoisomers Έ and Z.

The diastereoisomer of the E * configuration is separated from the diastereoisomer of the Z configuration by chromatography on a silica gel column, eluting with a mixture of ether, hexane and methylene chloride (5:45:50 by volume).

The diastereoisomer of the Z configuration has the following characteristics:

mp 86.5-88 ° C (hexane);

- infrared (film): characteristic absorption bands:

3400, 2975, 2920, 1690, 1500, 1450, 1390, 1365, 1250, 1175, 1080, 1050, 1020, 995, 920, 755 and 700 cm ^-1 ;

- H-nuclear magnetic resonance spectrum:

/ 300 MHz; CDCl 3, chemical shifts in ppm;

SK 277925-6

N (%)

5.32

5.34

H (%) 8.04 7.98

C (%)

68.41

68.15 coupling constants J in Hz (1.40 (s, 9H); 1.9 (s broad, 1H); 4.38 (pst, J = 4.6 and 4.8, 1H); 4.70 / s, 1ΗΛ520 / dt, J = 1.4 and 10.5, IHA, 526 / s, IHA, 5.34 / dt, J = 1.4 and 172, IHA, 5 , 86 / ddd.J = 5,4,10,5 and 1721, IHA, _n 724-7,37 years, 5HA,

- C-nuclear magnetic resonance spectrum:

/ CDCl ₃ / 28.12 / CH ₃ A, 58.74 / CHA,

75.33 (CHA, 79.58 / CA, 116.36 / CH3, 126.69 / CHA, 12726 / CHA, 128.32 / CHA, 137.17 / CHA, 139.96 (CA, 155.89) CA

- mass spectrum ä.c .// NH ₃ + isobutane /: 321 / M ⁺ + isobutane A, 281 (MH ⁺ + NH ₃ A 264 / MH +). base peak A, 246,225,208,190,64, 124,106;

- elemental analysis: calculated found

Diastereoisomer Z has the following characteristics:

- infrared spectrum (film):

characteristic absorbent bands:

3370, 3060, 2975, 2920, 1680, 1530, 1470, 1290, 1250, 1170, 1040, 1000, 930, 900, 870, 840, 755 _t and 700 cm -1;

- H-nuclear magnetic resonance spectrum:

/ 300 MHz; CDC1 _3; chemical shifts in ppm; coupling constants J in Hz (1.41 / s, 9HA, 1.8 (s broad JH)),

4.43 / psq, J = 0.9 and 4.4, IHA, 4.78 / s broad, IHA,

5.18 / dt, J = 1.2 and 10.5, IHA, 524 / s broad, IHA, 526 / dt, J = 12 and 17, IHA, 5.71 / ddd, J = 5.5, 10.5 and 17, IHA, _| 3,724-7.36 ta, 5HA,

- C-nuclear magnetic resonance spectrum:

/ CDC1 _3/2823 / _CH3 /; 5922 / CHA

75.33 / CHA, 79.85 / CA, 117.06 / CH ₂ A,

12729 / CHA, 127.56 / CHA

128.33 / CHA, 13627 / CHA, 138.14 / CA, 155.61 / CA,

C (%) 68.41

68.43

N (%) 5.32 5.08.

- elemental analysis: calculated found

H (%) 8.04 8.14

Example 3

In a 50 cm ³ , one-necked flask, under argon and equipped with a magnetic stirrer, was gradually introduced 526 mg (2.0 millimoles) of 1-phenyl-1-tert-butoxycarbonylamino-2-hydroxy-3-butene of configuration Cm, 20 cm ^{3 of} anhydrous methylene chloride, 1.9 cm ³ (20.0 millimoles) freshly distilled with ethyl vinyl acetate and 502 mg (02 millimoles) of pyridinium p-toluenesulfonate. The resulting homogeneous reaction mixture is allowed to react for 4.5 hours at a temperature near 20 ° C. Once the reaction is complete, one drop of pyridine is added and the reaction mixture is diluted with 60 cm ^{3 of} methylene chloride. The organic phase is washed twice with water and twice with saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulphate. After filtration, the solvents are removed under reduced pressure in a rotary evaporator. The residue is purified on a silica gel column, eluting with a hexane / ether (8/2, v / v) mixture. In 87% yield, 580 mg (1.73 mmol) of 1-phenyl-1-tert. butoxycarbonylamino-2- (1-ethoxyethoxy) -3-butene in the form of both epimers in the ratio 55/45, having the following characteristics:

melting point: 66-72 ° C;

- infrared spectrum (film): characteristic absorption bands at:

3370,2970,2925,2875, 1680,1520, 1495,1365, 1285,1250, 1170, 1080, 1050,1005,955, 930,890, _t 870,755 and 705 cm ^-1 ;

- H-nuclear magnetic resonance spectrum:

/ 300 MHz; CDC1 _3; chemical shifts in ppm; coupling constants J in Hz (0.9tain) and a 1.07 (possessing) 2t, J = 7.3HA, 1.55tain / and 122 taaj./Z2d, J=5.3tain./ and 5, 4 taut / 3HA, 1.40 (s, 9HA, 2.90-2.98 and 3.05-3.5 lta2H); 4,16 and 423 / 2psdd, J = 6,6 and 7, IHA, 4,31tain / a4,62 taaj.//2q, J=5,3/min./ and 5,4 taaj./,ΙΗΑ , 4.71 taaj. and 4.74tains / Z2m, 1HA, 522 and 523 / 2dt, J = 12 and 10.5, IHA, 5.25 and 5.30Z2dt, J = 12 and 17.4, IHA, 5.37 and 5.442m, IHA, 5.77tain / a 5.9 + ta / 2ddd, J = 7.10.5 and 17.4, IHA, 7,177.37ta, 5HA

Elemental analysis: C (%) calculated 68.03 found 68.00

H (%) N (%) 8.71 4.18 8.78 4.13.

Example 4

In a 15 cm ³ single neck flask maintained under argon and equipped with a magnetic stirrer, 251 mg (0.75 millimoles) of the E configuration of 1-phenyl-1-tert-butoxycarbonylamino-2- (1-ethoxyethoxy) -3- butene as a solution in 1.5 cm ^{3 of} acetonitrile. Thereafter, 1.5 cm @ ^{3 of} carbon tetrachloride, 225 cm @ ^{3 of} distilled water are added in succession, and sodium bicarbonate (409.5 mg, 4.875 mmol) is added with vigorous stirring. 882 mg (4.125 millimoles) of sodium periodate are then added in small portions. The reaction mixture was allowed to react with stirring for 5 minutes (gas evolution) followed by the addition of 25.1 mg (10 wt%) of ruthenium chloride in one portion. The mixture was allowed to react with vigorous stirring (blackish strongly heterogeneous mixture) for 48 hours at a temperature near 20 ° C.

The reaction mixture is then diluted with water to give a total volume of 12 cm ³ . The black basic aqueous phase is extracted three times with 20 cm @ ^{3 of} ether. The basic phase is then cooled to 0 ° C, followed by the dropwise addition of a 2M aqueous hydrochloric acid solution of 3 cm ³ dropwise in the presence of 30 cm ^{3 of} methylene chloride. The acidic aqueous phase obtained is extracted with 35 cm @ ^{3 of} methylene chloride. The organic phases are combined and washed three times with 8 cm @ ^{3 of} water, once with 10 cm @ ^{3 of} saturated aqueous sodium chloride solution. The organic phases are then dried over a 1: 1 by volume mixture of sodium sulfate and magnesium sulfate and filtered through celite under reduced pressure. The solvents are then removed under reduced pressure to reduce the volume to 5 to 8 cm 3. This residue is dried on a 4Ä molecular sieve. The organic phase is separated from the molecular sieve and the residual solvent is removed under reduced pressure in a rotary evaporator.

In 77% yield, 205 mg (0.58 mmol) of pure configuration E of 3-phenyl-3-tert-butoxycarbonylamino-2- (1-ethoxyethoxy) propionic acid is obtained as a pale yellow oil having the following characteristics:

- infrared spectrum (film): characteristic absorption bands at:

3700-2200, 3060.2980,

2930, 2850, 1720, 1660,

1602.1590, 1500.1450,

1400.1370, 1280.1250,

1170, 1080, 1050, 1030, 950, 930, 890 and 700 cm ^-1 ;

- H-nuclear magnetic resonance spectrum:

/ 300 MHz; CDCl; chemical shifts in ppm; frequency constants J in Hz /

0.81 and 1.04 (2t, J = 7.3H);

1.18 and 1.20 / 2d, J = 5.4, 3HZ;

1.42 (s, 9H);

2.60-2.88 and 3.15-3.52 (m ^ H),

4.35-4.50 and 4.65-4.80 (m, 1H); 5.29 (s broad, 1H), 5.72 (s broad, 1H); 7,13-7,38An, 5 H /; 8.52 / s W1H.

Claims (4)

PATENT CLAIMS A process for the stereoselective preparation of a lysoserine derivative of the general formula I NH-CO-R NH-CO-R The C 6 H 5 OH is subsequently protected for the hydroxyl group of the product and the alcohol thus protected is oxidized to give the phenylisoserine derivative of formula I in configuration E, the enantiomers of which are optionally separated. 2. The process of claim 1 wherein the benzoyl or tert-butoxycarbonyl group introducing agent is benzoyl chloride or di-tert-butyl dicarixmate, and reacted with benzylamine in an inert organic solvent such as methylene chloride in a in the presence of a mineral base such as sodium hydroxide or sodium bicarbonate or carbonate, or an organic base such as triethylamine or 4-dimethylaminopyridine. The process according to claim 1, wherein the acrolein is reacted with N-benzylamide or tert-butylbenzylcarbamate, pre-anionized with 2 equivalents of an organolithium derivative, such as sec-butyllithium, working in an inert organic solvent such as tetrahydrofuran at a temperature near -100 ° C. 4. The process of claim 1, wherein the hydroxyl group of the alcohol is first protected and then the alcohol thus protected is oxidized with an oxidizing agent selected from the group consisting of sodium periodate in the presence of a catalytic amount of a ruthenium derivative or potassium permanganate. The end of the document in which R is a phenyl radical or tert-butoxy radical and R is a hydroxyl protecting group, characterized in that benzylamine is treated with a reagent to introduce a benzoyl or tert-butoxycarbonyl group to give a product of the formula: C ₆ H ₅ NH-CO-R, which is treated with acrolein after a double anionisation to form an alcohol of formula: in the form of a mixture of configurations E and Z, separating configuration E of the formula: